S-substituted n-benzhydryl pseudothioureas and their pseudothiouronium salts



ZfiliLSllS Patented Oct. 27, 1959 See S-SUBSTITUTED N-BENZHYDRYLPSEUDUTHIO- UREASS AND THElR PSEUDOTHIOURONIUM SALT Stanley 0. Winthrop,Montreal, Quebec, Canada, assignor to American Home ProductsCorporation, New York, N.Y., a corporation of Delaware No Drawing.Application February 17, 1958 Serial No. 715,518

6 Claims. (Cl. 260- 564) This invention relates to new S-subst'itutedderivatives of N-benzhydryl thiourea and to salts of these derivatives.The substituent attached to sulfur is one selected from the group whichconsists of lower alkyl (up to four carbon atoms) and benzyl.

This applicationis a continuation-in-part of my copending application,Serial No. 562,662, filed February 1, 1956, now abandoned.

My invention also relates to the preparation of these new chemicalcompounds; and it is also concerned with a new and improved method forpreparing N-benzhydryl thiourea, an intermediate used in the preparationof these new compounds.

The new compounds possess valuable pharmacological properties, beingparticularly suitable as stimulants for the central nervous system ofboth animals and human beings. in the amounts administered for thesepurposes they are non-toxic. Many of these compounds also possess musculotropic activity of a high order.

My new chemical compounds, in base form, may be represented by thegeneric structural formula:

wherein R represents a radical selected from the group which consists oflower alkyl and benzyl radicals. However it will be understood that thisstructural formula represents the new bases in one of the tautomericforms, and that the compounds, in a different tautomeric form, may bestructurally represented by a somewhat different formula.

My invention also relates to salts of these S-substituted pseudothioureabases, more particularly to the acid addition salts of these bases.

The acid addition salts, i.e. the N-benzhydryl-S-loweralkylpseudothiouronium or N-benzhydryl-S-benzylpseudothiouronium salts,may be represented by the structural formula:

by the addition of an acid such as a h'ydrohalic acid, maleic acid,acetic acid, sulfuric acid, etc. to the S- substitutedN-benzhydryl-pseudothiourea base, or by reacting a lower alkyl or benzylester of an inorganic acid, such as methyl iodide, dimethyl sulfate orbenzyl chloride, with N-benzhydryl thiourea. The resulting com pounds,both in base form, and in the form or" their nontoxic salts, aretherapeutically active, being stimulants for the central nervous systemsof both man and animal, as well as showing musculotropic action. All ofthe salts disclosed herein are relatively non-toxic to human beings, andthey may be utilized, as equivalent to the corresponding bases, intherapeutically effective amounts Without objectionable toxic eflfects.V

N-benzhydryl thiourea .is a convenient starting material for preparingmy new chemical compounds. This intermediate may be prepared by themethod of Wheeler, see the American Chemical Journal, volume 26 (1901),page 353; or by the method of Kaye et 211. as :described in J.A.C.S.,volume 74- (1952), pages 403 to 407.

I have also found that this intermediate, N-benzhydryl thiourea, may beconveniently prepared by fusing =be'nzhydrylamine hydrochloride andammonium thiocyanate in approximately equimolar proportions. Afterfreeing the reaction mixture from water-soluble by-produc'ts, theinsoluble N-benzhydryl thiourea may be recovered in crystalline form.

In preparing my therapeutically active compounds in the form of the freebase, i.e. in preparing an N-benzhydryl-S-lower alkylpseudothiourea, orN-benzhydryl- S-benzylpseudothiourea, various N-benzhydryl-Sdoweralky-land N-benzhydryl-S-benzyl pseudothiouroniuin salts may first beprepared, and. the free bases then liberated therefrom by treatment withan alkali. .A mild alkali, such as an alkali metal carbonate, ispreferably used. This process may be readily carried out at roomtemperature in a suitable solvent, such as methanol.

The S-substituted-N-benzhydryl pseudothiouronium salts may be preparedby reacting N-benzhydryl thiourea with the'lower alkyl or benzyl esterof an inorganic acid, such as methyl iodide, dimethyl sulfate, or benzylchloride. This is conveniently accomplished by bringing the reactantstogether in a suitable solvent, such as methanol. As the reactionproceeds only slowly at room temperature, it is preferable to refiux thereaction mixture for a few hours, whereupon the S-lower alkyloiS-benzyl-substit1ited N-benzhydryl pseudothiouronium salt precipitatesin the solvent. It may be removed therefrom and purified byrecrystallization.

My new N-benzhydryl-S-loWer alkylpseudothiouronium salts, andN-benzhydryl-S-benzylpseudothiouronium salts, may also be prepared byreacting the free base with an acid. Hydrohalic acid salts, as well assalts of inorganic acids such as sulfuric, and salts of organic acidssuch as maleic and acetic acids, may be readily prepared by thisprocedure.

The N-benzhydryl-S-lower alkylpseudothiourea base, or N benzhydryl Sbenzylpseudothiourea, may be brought into contact with the salt-formingacidin a suitable solvent. The resulting salt, formed in the chemicalreaction ensuing, is then recovered. Various solvents may be utilized,in the reaction, but ordinarily I prefer to use-methanoLor a mixture ofacetone andether. The reaction, in all cases, proceeds readily at roomtemperature and maintenance of an elevated temperature is not essential.The crude salt precipitates in the reaction mixture, and it may then berecovered and purified by recrystallization from a suitable solvent, orfrom a suitable solvent mixture, such as from isopropanol, or frommixedethanol-ether.

3 l The following examples are illustrative of my invention:

EXAMPLE 1 N-bertzhydryl thiourea 107 grams (0.49 mole) ofbenzhydrylarnine hydrochloride and 41.1 grams (0.54 mole) of ammoniumthiocyanate were fused together for two hours. Fusion temperatures overthe range 125 C. to 160 C. are suitable. For highest yields, however, itis preferred to fuse the reactants together at a temperature of about140 C. The fusion periods may vary, but at the end of two hours thereaction is usually complete.

The reaction mixture was then treated with boiling water to extractwater-soluble materials. The insoluble material remaining was filteredoft, dissolved in isopropanol, and recrystallized from this solvent toyield 67 grams of N-benzhydryl thiourea. A typical sample of the crudeproduct melted at 173-175 C. Although not necessary for use in thesubsequent reactions, an analytically pure sample may be prepared by tworecrystallizations of the product from ispropanol, the pure productmelting at aproximately 186-188" C.

EXAMPLE 2 N-benzhydryl-S-methylpseudozhiouronium methylsulfate 12.0grams (0.05 mole) of N-benzhydryl thiourea and 3.15 grams (0.025 mole)of dimethyl sulfate were dissolved in 100 milliliters of methanol andrefluxed for three hours. On cooling and evaporating down, an oilresidue remained in the reaction mixture, and this oil solidified onstanding in ether. The product was N- benzhydryl Smethylpseudothiouroninm methylsulfate, and a typical sample of the crudeproduct melted at 110-118 C. The crude product was then dissolved inisopropanol and recrystallized twice from this solvent to give asubstantially pure product which melted at 130.5-132" C. Analyses forcarbon nitrogen sulfur and hydrogen confirmed the empiric formula C H NS O EXAMPLE 3 N-benzhydryl-S-methylpseudothiouronium iodide 2.4 grams(0.01 mole) of N-benzhydryl thiourea and 1.4 grams (0.01 mole) ofmethyliodide were dissolved in 100 milliliters of methanol and refluxedfor six hours. On cooling and addition of ether, a solid productprecipitated. 3.5 grams of this crude product, a typical sample of whichmelted at 182184 C. was thus recovered. This product,N-benzhydryl-S-methylpseudothiouronium iodide, was then dissolved in andrecrystallized from isopropanol. After two recrystallizations thesubstantially pure product melting at 178.5-180 C. was secured. Analysesfor iodine, sulfur and nitrogen confirmed the empiric formula C H N SI.

EXAMPLE 4 N-benz'hydryl-S-methylpseudothiourea 46 grams (0.12 mole) ofN-benzhydryl-S-methyb pseudothiouronium iodide was dissolved in a literof methanol and enough of a 10 percent solution of sodium carbonate wasthen added to liberate the free base. This precipitated as a solidproduct and was removed from the methanol.

It was first washed with water and then twice recrystallized frombenzene to yield substantially pure N-benzhydryl-S-methylpseudothiourea, melting at 161-162 C. Analysis fornitrogen and sulfur confirmed the empiric formula C H N S.

EXAMPLE N-benzhydryl-S-methylpseudothiouronium chloride 3 grams (0.012mole) of N-benzhydryl-S-methylpseudothiourea was dissolved in a mixturecomprising 50 mlllrhters of acetone and 50 milliliters of ether.

4 excess amount of an etheral solution of hydrogen chloride was thenadded. A solid product which melted at 195-196 C. was precipitated inthe reaction mixture- After recrystallization from a mixture of ethanolandether, the substantially pure salt,N-benzhydryl-S-methylpseudothiouronium chloride, melting at 195-196" C.was obtained. Analyses for nitrogen, sulfur and chlorine confirmed theempiric formula C H N SCl.

EXAMPLE 6 N-benzhydryl-S-methylpseudothiouronium maleate 3 grams (0.012mole) of N-benzhydryl-S-methylthi ourea was dissolved in a mixture of 50milliliters of acetone and 50 milliliters of ether. 0.9 gram (0.0077mole) of maleic acid, which had previously been dissolved in a littleether, was then added to the solution. This re sulted in a solidprecipitate of crude N-benzhydryl-S- methylpseudothiouronium maleate, atypical sample of which melted at l66.5l7l C. The product was then twicerecrystallized from a mixture of ethanol and ether to give substantiallypure N-benzhydryl-S-methylpseudothiouronium maleate, a typical sample ofwhich melted at 164-165 C. Analyses for nitrogen and sulfur confirmedthe empiric formula C H N SO EXAMPLE 7N-benzhydryZ-S-methylpseudothiouronium bisulfate 3.0 grams (0.012 mole)of N-benzhydryl-S-methylpseudothiourea were dissolved in 50 millilitersof acetone, and a slight excess of sulfuric acid was added to thesolution. Upon the addition of ether, a solid product, melting at204-205 C., precipitated. This solid product wasN-benzhydryl-S-methylpseudothiouronium bisulfate. By recrystallizationfrom isopropanol. there was obtained 2.6 grams of purified productmelting at 202-203 C. (dec.). Analysis confirmed the empiric formula 15l8 2 2 2- EXAMPLE 8 N-benzhydryl-S-methylpseudothiouronium acetate 3.0grams (0.012 mole) of N-benzhydryl-S-methylpseudothiourea were dissolvedin 50 milliliters of acetone and a slight excess of acetic acid wasadded to the solution. The acetone was removed in vacuc, i.e. at areduced pressure less than atmospheric, the residue was crystallized bytrituration with ether. The product resulting wasN-benzhydryl-S-methylpseudothionronium acetate. By recrystallizationfrom ethyl acetate, there was obtained 2.1 grams of the purified productmelting at 144-145 C. (dec.). Analysis confirmed the empiric formulaC17H20N2SO2.

EXAMPLE 9 N-benzhydryl-S-methylpseztdothiouronium bromide 3.0 grams(0.012 mole) of N-benzhydryl-S-methylpseudothiourea were dissolved in 50milliliters of acetone and a slight excess of hydrobromic acid was addedto the solution. Upon the addition of ether a solid productprecipitated. This product was N-benzhydryl-S-methylpseudothiouroniumbromide. By recrystallization from acetonitrile there was secured 2.5grams of a purified product melting at l98.5199.5 C. Analysis confirmedthe empiric formula C15H17N2SBI.

EXAMPLE 10 N-benzhydryl-S-ethylpseudothiouronium iodide 2.4 grams (0.01mole) of N-benzhydryl thiourea and 2.3 grams (0.015 mole) of ethyliodidewere dissolved in milliliters of ethanol and the mixture refluxed for 3hours. Upon cooling and addition of ether to the solution, an oilprecipitated. This oil solidified on standing. The product wasN-benzhydryl-S-ethylpseudothiouronium iodide and, after tworecrystallizations from isopropanol- ,ether, the purifltid P QSi JS lmelting at l45147 C. was

secured. Analysis confirmed the empiric formula, CIBHZQNQSI' EXAMPLE llN-benzhydryl-S-propylpseudothiouronium iodide The procedure followed inmaking this compound was similar to that given in Example 10.

4.84 grams (0.02 mole) of N-benzhydryl thiourea and 5.1 grams (0.03mole) of propyliodide were refluxed in 200 milliliters of acetone forsix hours. There was thus secured 6.0 grams of the product,N-benzhydryl-S- propylpseudothiouronium iodide in the form of fineneedles, melting at ISO-151 C. Analysis confirmed the empiric formula CI-I N SL EXAMPLE 12 N -benzhydryl-S-propylpseudothiourea 1.0 gram ofN-benzhydryl-S-propylpseudothiouronium iodide, as prepared in Example11, was dissolved in aqueous methanol and a solution of sodium carbonatewas added. The free base, N-benzhydryl-S-propylpseudothiourea,precipitated and was filtered off and washed with water. It melted at75-77 C. Analysis confirmed the empiric formula C H N S.

EXAMPLE 13 N-benzhydryl-S-isopropylpseudothiouronium iodide 2.4 grams(0.01 mole) of N-benzhydryl thiourea and 2.5 grams (0.015 mole) ofisopropyliodide were dissolved in 75 milliliters of ethanol and thesolution was refluxed for 5 hours. The solution was then cooled andether added, whereupon a solid product precipitated. This product wasN-benzhydryl-S-isopropylpseudothiouronium iodide. Upon recrystallizationfrom isopropanol-ether the purified product melting at 185-18'6.5 C.resulted. Analysis confirmed the empiric formula C H N SI.

EXAMPLE 14 N-benzhydryl-S-butylpseudothiouronium iodide By following theprocedure described in Example 11 and starting with 4.84 grams (0.02mole) of N-benzhydryl-thiourea and 5.5 grams (0.03 mole) of butyliodidethere was obtained 6.4 grams of N-benzhydryl-S-butylpseudothiouroniurniodide in the form of fine needles melting at 160-161" C. Analysisconfirmed the empiric formula CmHzgNzSI- EXAMPLE 15N-benzhydryl-S-butylpseudothiourea By following the procedure describedin Example 12 and starting with 1 gram ofN-benzhydryl-S-butylpseudothiouronium iodide, as prepared in Example 14,there was obtained 0.6 gram of the free base,N-benzhydryl-S-butylpseudothiourea. The compound melted at 77-79 C. andanalysis confirmed the empiric formula CIQHnNzS- 6 EXAMPLE 16N-benzhydryl-S-benzylpseudothiouronrium chloride EXAMPLE 17 N-benzhydryl-S-benzy lpseudathiozirea By following the proceduredescribed in Example 12, and treating theN-benzhydryl-S-benzylpseudothiouronium chloride, as prepared in Example16, with a solution of sodium carbonate in aqueous methanol, the freebase was obtained. This was N-benzhydryl-S-benzylpseudothiourea, meltingat 94-97 C. Analysis confirmed the empiric formula C H N S.

I claim:

1. A compound selected from the group which consists of bases of theformula CH.NH.G=NH

where R is selected from the group consisting of lower alkyl and benzyl,and the chloride, bromide, iodide,

methyl sulfate, bisulfate, acetate and maleate salts thereof.

2. N-benzhydryl-S-methylpseudothiourea. 3.N-benzhydryl-S-propylpseudothiourea. 4.N-benzhydryl-S-butylpseudothiourea. 5.N-benzhydryl-S-benzylpseudothiourea. 6.N-benzhydryl-S-isopropylpseudothiouronium iodide.

References Cited in the file of this patent UNITED STATES PATENTS Hahlet al. Aug. 6, 1929 Schubert et a1. July 13, 1937 OTHER REFERENCESSchroeder: Chem. Reviews, vol. 55, pp. 181-221 (1955).

Kaye et al.: J.A.C.S., vol. 74, pp. 403-407 (1952).

Wheeler: American Chemical Journal, vol. 26 (1901), p. 353.

Borovicka 5 et al.: Chemical Abstracts, vol. 45, p. 577

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OF BASES OF THEFORMULA
 2. N-BENZHYDRYL-S-METHYLPSEUDOTHIOUREA.